Defects in oxidative phosphorylation (OXPHOS) have been associated with various neuromuscular degenerative processes. We propose to take advantage of current methodology that allows the manipulation of nuclear genes in embryonic stem cells and generate and characterize of mouse models with conditional mutations in nuclear-coded OXPHOS genes. The general hypotheses and questions this proposal will test are: i) What are the specific role of the knocked out factors on OXPHOS assembly and function? ii) Are different cell populations more susceptible to defects in specific OXPHOS complexes? iii) Do defects in specific respiratory chain complexes in muscle or nerves lead to different muscular or neurodegenerative phenotypes? iv) Are these phenotypes associated with different levels of oxidative damage or protein aggregation? Specifically, we will develop knock in mice for three respiratory complex genes in which an evolutionarily conserved exon is flanked by IoxP sites. The following genes will be manipulated: the NDUFS1 gene (complex I), Iron-Sulfur Protein (complex III) and COX10, a protoheme O farnesyl-transferase (required for heme a production and complex IV activity). The knockin animals will be crossed with mice expressing Cre-recombinase driven by CNS and skeletal muscle promoters. We expect these studies to provide evidence that specific defects in the OXPHOS can manifest as distinct phenotypic alterations.